Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients:Systematic review and meta-analysis

BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease.Post-transplant diabetes mellitus(PTDM)is a common complication in solid organ transplant recipients,and significantly compromises long-term survival beyond a year.AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus,51242 on Cyclosporine and 3020 on Sirolimus.Random effects meta-analyses was used to calculate incidence.RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus(OR=1.495%CI:1.0–2.0)and sirolimus(OR=1.8;95%CI:1.5–2.2)than with Cyclosporine.The overall incidence of PTDM at years 2-3 was 17%for kidney,19%for liver and 22%for heart.The risk factors for PTDM most frequently identified in the primary studies were age,body mass index,hepatitis C,and African American descent.CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term(2-3 years post-transplant),whereas sirolimus exhibits higher diabetogenicity in the longterm(5-10 years post-transplant).This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.

Overexpression of fibrinogen-like protein 2 protects against T cell-induced colitis

AIM To determine the effect of overexpression of fibrinogenlike protein 2(FGL2) on regulatory T cell(Treg) and effector T(Teff) cell function on T cell-induced colitis in Rag1-/-mice.METHODS Treg and Teff cells from fgl2-/-, fgl2+/+, and fgl2 Tg mice were purified by FACS. They were studied in vitro for immunosuppressive activity and cell proliferation and in vivo for their effects on the development and prevention of T cell-induced colitis in Rag1-/-mice. RESULTS In vitro, fgl2 Tg Treg had enhanced immunosuppressive activity, and fgl2 Tg Teff had reduced proliferation to alloantigen stimulation. Transfer of Teff from C57Bl/6J mice(fgl2+/+) into Rag1-/-mice produced both clinical and histologic colitis with dense infiltrates of CD3+ T cells, crypt abscesses and loss of goblet cells. Fgl2 Tg Treg prevented the development of T cell-induced colitis, whereas fgl2+/+ and fgl2-/-Treg were only partially protective. In mice that received fgl2 Tg Treg, the ratio of Foxp3+ to CD3+ cells was increased both in the colon and in mesenteric lymph nodes, and Teff cell proliferation as determined by staining with Ki67 was reduced. Teff cells from fgl2 Tg mice did not produce colitis. CONCLUSION Here we show that fgl2 Tg Teff are hypoproliferative and do not induce colitis. We further demonstrate that fgl2 Tg Treg prevent colitis in contrast to fgl2+/+ Treg, which were only partially protective. These studies collectively provide a rationale for exploring the use of FGL2 or Treg expressing high levels of FGL2 in the treatment of inflammatory bowel disease.

Epigenetic basis of hepatocellular carcinoma: A network-based integrative meta-analysis

AIM To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis.METHODS Pub Med and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks. Pathway enrichment analysis was performed using IPA, which also provides literature-driven and computationallypredicted annotations for significant association of genes to curated molecular pathways.RESULTS From an initial 928 potential abstracts, we identified and analyzed 11 eligible high-throughput methylation datasets representing 354 patients. A significant proportion of studies did not provide concomitant clinical data. In the promoter region, HIST1H2AJ and SPDYA were the most commonly methylated, whereas HRNBP3 gene was the most commonly hypomethylated. ESR1 and ERK were central genes in the principal networks. The pathways most associated with the frequently methylated genes were G-protein coupled receptor and c AMP-mediated signalling. CONCLUSION Using an integrative network-based analysis approach of genome-wide DNA methylation data of both the promoter and body of genes, we identified G-protein coupled receptor signalling as the most highly associated with HCC. This encompasses a diverse range of cancer pathways, such as the PI3 K/Akt/m TOR and Ras/Raf/MAPK pathways, and is therefore supportive of previous literature on gene expression in HCC. However, there are novel targetable genes such as HIST1H2 AJ that are epigenetically modified, suggesting their potential as biomarkers and for therapeutic targeting of the HCC epigenome.

Integrative analysis of layers of data in hepatocellular carcinoma reveals pathway dependencies

BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma(HCC).AIM To comprehensively analyze and characterize all publicly available genomic,gene expression,methylation,miRNA and proteomic data in HCC,covering 85 studies and 3355 patient sample profiles,to identify the key dysregulated genes and pathways they affect.METHODS We collected and curated all well-annotated and publicly available highthroughput datasets from PubMed and Gene Expression Omnibus derived from human HCC tissue.Comprehensive pathway enrichment analysis was performed using pathDIP for each data type(genomic,gene expression,methylation,miRNA and proteomic),and the overlap of pathways was assessed to elucidate pathway dependencies in HCC.RESULTS We identified a total of 8733 abstracts retrieved by the search on PubMed on HCC for the different layers of data on human HCC samples,published until December 2016.The common key dysregulated pathways in HCC tissue across different layers of data included epidermal growth factor(EGFR)andβ1-integrin pathways.Genes along these pathways were significantly and consistently dysregulated across the different types of high-throughput data and had prognostic value with respect to overall survival.Using CTD database,estradiol would best modulate and revert these genes appropriately.CONCLUSION By analyzing and integrating all available high-throughput genomic,transcriptomic,miRNA,methylation and proteomic data from human HCC tissue,we identified EGFR,β1-integrin and axon guidance as pathway dependencies in HCC.These are master regulators of key pathways in HCC,such as the mTOR,Ras/Raf/MAPK and p53 pathways.The genes implicated in these pathways had prognostic value in HCC,with Netrin and Slit3 being novel proteins of prognostic importance to HCC.Based on this integrative analysis,EGFR,andβ1-integrin are master regulators that could serve as potential therapeutic targets in HCC.